Evaluation of mycophenolate mofetil for initial treatment of chronic graft-versus-host disease

Martin, Paul J.; Storer, Barry E.; Rowley, Scott D.; Flowers, Mary E.D.; Lee, Stephanie J.; Carpenter, Paul A.; Wingard, John R.; Shaughnessy, Paul; Devetten, Marcel P.; Jagasia, Madan; Fay, Joseph W.; Besien, Koen van; Gupta, Vikas; Kitko, Carrie L.; Johnston, Laura; Maziarz, Richard T.; Arora, Mukta; Jacobson, Pamala A.; Weisdorf, Daniel J.

doi:10.1182/blood-2009-02-202937

Cited by 145 publications

(125 citation statements)

References 41 publications

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“…A retrospective study of de novo and steroid-refractory cGVHD has shown response rates of 90 and 75 %, respectively [139]. In a randomized prospective trial of MMF vs placebo in addition to other treatment for cGVHD, the study was terminated early due to no difference in response rate in control and study arms [140]. Common side effects of MMF include cytopenias, infections and gastrointestinal toxicity which can mimic aGVHD.…”

Section: Mycophenolate Mofetil (Mmf)mentioning

confidence: 99%

State-of-the-art acute and chronic GVHD treatment

Jamil

Mineishi

2015

Int J Hematol

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owing to the advancement in reduced intensity conditioning (RIC) and in patients without HLA-matched donors due to the use of cord blood and haploidentical HSCT [4][5][6]. Although marked improvement has been made in supportive care, immunosuppressive therapy and DNA-based Human Leukocyte Antigen (HLA) typing, graft vs host disease (GVHD) remains a major cause of morbidity and non-relapse mortality among allogeneic HSCT recipients. It was first described by Billingham in 1966 as a syndrome where immunocompetent T cells from the donor recognize and damage the host tissue in an immunocompromised recipient. It presents with heterogeneous symptoms involving multiple organ systems including gastrointestinal tract, skin, mucosa, liver and lungs [7]. In the past clinical features occurring within 100 days after HSCT was called acute GVHD (aGVHD) and those happening after 100 days were labeled chronic GVHD (cGVHD) [8,9]. This definition was rather unsatisfactory thus National Institute of Health (NIH) consensus criteria were developed and have been revised. The criteria have added new categories such as late-onset aGVHD (acute GVHD occurring after 100 days) and overlap syndrome which includes features of both acute and chronic GVHD to the classification, and also have introduced new definitions for organ system involvement [10][11][12]. The categorization of acute vs chronic GVHD is based on the combination of clinical symptoms rather than the time of onset. Depending upon a number of variables associated with patients, donors, and types of transplant, the incidence of aGVHD varies with incidence of grade II-IV GVHD at 40 % in matched related donor (MRD) transplant to 50 % in MUD transplant. The main risk factors for aGVHD include degree of HLA mismatch, age of the patient, previous all immunization of the donor and the kind of GVHD prophylaxis used. About 30-70 % of allogeneic HSCT recipients alive after 100 days will Abstract Graft-versus-host disease (GVHD) remains as the major obstacle for successful hematopoietic stem cell transplant (HSCT). Roughly half of the patients undergoing HSCT develop GVHD which requires treatment, and above 10 % of the patient may die because of it. However, GVHD presents with anti-tumor activity, called graft-versus-tumor (GVT) effect, and it carries significant anti-tumor activity, thus suppressing GVHD completely may increase the relapse of original disease. Thus, it is important to control GVHD to the appropriate level.

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Section: Mycophenolate Mofetil (Mmf)mentioning

confidence: 99%

State-of-the-art acute and chronic GVHD treatment

Jamil

Mineishi

2015

Int J Hematol

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“…Examples include daclizumab that seems effective in corticosteroid-resistant aGVHD but detrimental when added to corticosteroids as initial therapy or mycophenolate that is ineffective when added to steroids for the initial treatment of cGVHD. 87,88 Reasons for this are complex and incompletely understood. Its possible corticoisteroid-resistant cases of GVHD are biologically different than untreated cases.…”

Section: Pomalidomidementioning

confidence: 99%

Chronic GVHD: Where are we? Where do we want to be? Will immunomodulatory drugs help?

Linhares

Pavletić

Gale

2012

Bone Marrow Transplant

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Chronic GVHD (cGVHD) is an important problem after allotransplants. Some risk factors for cGVHD are similar to those of acute GVHD (aGVHD) but others are distinct indicating sometimes overlapping but unique pathogeneses. Precise incidence and prevalence data of cGVHD are lacking because of diverse diagnostic criteria but a 50% risk is a reasonable estimate. Incidence and prevalence of cGVHD are probably growing because of increased use of unrelated donors, blood rather than bone marrow (BM) grafts, decreased early transplant-related mortality (TRM) and increasing frequency of allotransplants. Pathophysiology of cGVHD is complex and poorly understood. Notably, no reliable surrogate end point to predict mechanism(s) of cGVHD has been identified. Therapy of cGVHD is unsatisfactory. Corticosteroids are effective but other drugs are controversial and few are rigorously tested in randomized trials. Highly variable response rates are reported because of small sample sizes and inconsistencies in eligibility, diagnostic and response criteria. We focus on the possible role of immunomodulatory drugs (IMiDs), thalidomide lenalidomide and pomalidomide, in preventing and treating cGVHD. The data suggest activity of thalidomide but at doses not clinically practical in many instances. There are few data with lenalidomide. Trials of pomalidomide, which has immune activities like thalidomide but with fewer adverse effects, are beginning. Because cGVHD is not recently reviewed in Bone Marrow Transplantation, we give a brief background and discuss challenges in diagnosing, understanding and treating cGVHD including the recently proposed National Institutes of Health consensus criteria for cGVHD. 1-3 It occurs in about 50% of persons surviving 41 year post transplant and causes substantial morbidity and mortality. There has been little progress over the past 30 years in preventing and/or treating cGVHD. Moreover, incidence and prevalence are increasing because of several factors including: (1) increased use of blood cell rather than BM grafts; (2) increasing use of incompletely HLA-matched related and unrelated donors; (3) increased use of donor-lymphocyte infusions, especially in the context of reduced-intensity allotransplants; (4) increased number of transplants done each year; and (5) increased proportion of transplants in older persons. [4][5][6] The focus of our review is on the use and potential of IMiD-class drugs to prevent and/or treat cGVHD. These drugs have unique, complex immune regulatory activities. As a prelude, we review some relevant definitional, laboratory and clinical features of cGVHD.

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“…O uso de micofenolato mofetil (MMF) associado ao tratamento inicial foi avaliado em estudo duplo-cego randomizado, 28 fechado em 2008, após análise de resposta (resolução de DECH-c) em 151 pacientes (23% -grupo MMF vs 18% -controles, NS). A comparação da taxa de retirada de imunossupressão em dois anos também não mostrou evidên-cia de benefício em associar o MMF ao esquema inicial para DECH-c (DIa).…”

Section: Tratamento Da Dech-c Moderada E Graveunclassified